Alcohol or ethanol produces a change in the redox state of the hepatocyte by rapidly converting NAD plus to NADH. Such an change would be unfavorable for the proper functioning of NAD plus dependent dehydrogenase systems. The glucuronide conjugation requires continuous generation of uridine diphospho- glucuronic acid (UDPGA). UDPGA is a product of a reaction that is catalyzed by UdP-glucose dehydrogenase an enzyme that is dependent on NAD plus. Synthesis of UDPGA also needs glucose as precursors. Under certain conditions, ethanol inhibits gluconeogenesis in the liver and this action may limit the supply of glucose. The shift in the NAD plus/NADH ratio in the direction of reduction and the inhibition of gluconeogenesis by ethanol would decrease the capacity of the animal to form glucuronides by reducing the amount of UDPGA made available for the conjugation. Under these conditions the pharmacologic activity of drugs that are primarily inactivated by glucuronide conjugation would most likely be affected. Morphine, salicylic acid, salicylamide, acetaminophen and indomethacin are conjugated directly to inactive glucuronides. The objective of this project is, first, to investigate the effect of acute and chronic ethanol intake on the glucuronic acid conjugation of these drugs and, secondly, to correlate any observed changes in the glucuronide conjugationon the pharmacologic activity of these drugs. Both in vivo and vitro experiments will be conducted in laboratory animals to achieve these objectives.